Major depressive disorder ( MDD) is one of the most common psychiatric disorders. It is characterized by psychological, physical and behavioral symptoms that can be complex and vary widely between individuals.
Typically, these patients experience a prolonged period of low mood, often accompanied by low self-esteem, loss of interest, feelings of hopelessness, and low energy.
It exerts a significant burden on the patient, with negative impact on health-related quality of life, impairments in multiple domains of cognitive function, premature mortality due to a variety of physical disorders, and suicide in approximately 4% to 15% of patients. patients.
Patients with MDD often experience impaired cognitive function in several domains, such as executive functioning, processing speed, concentration/attention, learning, and memory.
They may experience cognitive impairment not only before and during depressive episodes but also after remission of symptoms. These deficiencies can lead to debilitating problems such as missed work days, poor academic performance, and reduced ability to perform daily tasks.
The Diagnostic and Statistical Manual 5 lists impairment in cognition (decreased ability to think or concentrate, or indecisiveness) as diagnostic criteria for MDD.
Many clinical studies with antidepressants suggest that serotonin and norepinephrine reuptake inhibitors (SNRIs), including duloxetine and other antidepressants such as vortioxetine, bupropion, and moclobemide, may improve cognitive function in depression.
Vortioxetine, a novel antidepressant with multimodal activity, has shown evidence of cognitive benefit in animal models as well as in patients with MDD.
Numerous studies have investigated cognitive function in depression in a variety of cognitive domains, including attention, processing speed, executive function, and memory. However, there is limited evidence on the comparative effectiveness of antidepressants on cognitive symptoms, mainly due to the diversity of tools used in clinical trials that create heterogeneous results.
The objective of this study was to evaluate the comparative effect of a variety of antidepressants on cognitive dysfunction, measured by the DSST test , in patients with MDD through a systematic review of the literature and a network meta-analysis (MAR). The DSST is the most used and validated cognitive test in neuropsychology.
Results are presented comparing various classes and individual antidepressants versus placebo in improving cognitive dysfunction as assessed on the DSST.
| Development of the evidence network and MAR |
The evaluation approach was chosen from studies that evaluate the same cognitive test, regardless of the cognitive domain. The subsequent analyzes and results presented for the MAR were performed from clinical trials that used the DSST.
The DSST is a “pencil and paper” cognitive test that assesses several aspects of cognitive function that are impaired in patients with MDD, such as executive function, processing speed, attention, and working memory. It is sensitive to change during effective treatment of MDD.
To simultaneously evaluate the comparative effects of more than 2 treatments, a MAR was performed. A MAR synthesizes direct and indirect comparisons across an entire network of treatments, allowing all available evidence to be considered in a single analysis. The outcome variable was the standardized mean change on the DSST from baseline to the end of the study.
| Results |
The review focused on 72 randomized clinical trials (RCTs) that evaluated pharmacological interventions, based on pre-specified eligibility criteria.
Interventions evaluated in the studies included SSRIs (citalopram, escitalopram, fluoxetine, paroxetine, sertraline, or fluvoxamine), selective serotonin and norepinephrine reuptake inhibitors (SNRIs) (duloxetine, venlafaxine, desvenlafaxine, or levomilnacipran), monoamine oxidase inhibitors (phenelzine or tranylcypromine), tricyclic antidepressants (desipramine, amitriptyline, imipramine, trimipramine or tianeptine), tetracyclic antidepressants (mianserin or mirtazapine) or non-SSRI/SNRI antidepressants (agomelatine, bupropion, reboxetine or vortioxetine).
> DSST as a single cognitive measure for the developmental network. Although there was great variation in the cognitive measures used in the RCTs, the DSST was the only cognitive endpoint in the studies reviewed that could be used as a test of cognitive dysfunction to develop a homogeneous mood and a "stable" network of evidence. .
The total number of patients in the RCTs in which the DSST was performed as a primary or secondary cognitive endpoint ranged from 27 to 602, the mean age varied between 36.6 and 79.6 years, and the percentage of men among the 24% and 58%.
The timing of DSST assessment across studies ranged from 3 to 24 weeks after baseline assessment. The antidepressants evaluated were SNRIs (duloxetine [707 patients]), SSRIs (citalopram [84 patients], escitalopram [54 patients], fluoxetine [127 patients], sertraline [240 patients]), MAOIs (phenelzine [28 patients]), antidepressants tricyclics (TCA) (desipramine [9 patients], nortriptyline [102 patients]) and non-SSRI/SNRI (vortioxetine [725 patients]).
Vortioxetine and duloxetine had the largest number of subjects in whom cognition was assessed by the DSST. The majority (9 of 12) of the studies included a placebo control.
A critical appraisal of the included studies was carried out using comprehensive assessment criteria based on the recommendations of the NICE guidelines. As a result, 2 networks were created for studies using the DSST: one network by drug class and one by antidepressant type.
> SEA. In class analysis, SSRIs, MAOIs and TCAs showed a smaller effect on DSST than placebo and TCAs showed a significantly worse effect on DSST than placebo. Vortioxetine and SNRIs were the only antidepressants that showed an improvement in DSST versus placebo, and this difference was statistically significant.
When comparing individual antidepressants vs. placebo, vortioxetine, duloxetine and sertraline showed an improvement in the DSST, with vortioxetine being the only antidepressant that showed a statistically significant difference.
The differences for duloxetine and sertraline vs. placebo were not statistically significant. All other antidepressants demonstrated a minor effect on cognitive dysfunction compared to placebo.
The 2 most effective antidepressants in terms of improvement on the DSST were vortioxetine and duloxetine, but duloxetine was not significantly different from placebo. Placebo was the third most effective, highlighting the fact that many antidepressants have less impact on cognitive function than placebo.
The analysis showed that vortioxetine was numerically more effective in terms of change in DSST from baseline than all other antidepressants included in the analysis. The probability that vortioxetine had a greater change in DSST from baseline than all other antidepressant classes (including placebo) was 97%.
| Discussion |
The effects of antidepressants on cognitive function are not yet fully understood, but the FDA has recently identified cognitive dysfunction as a target for drug treatments in patients with MDD.
The MAR findings showed that vortioxetine, duloxetine, sertraline and the SNRI class improved cognitive function measured with the DSST vs. placebo, with vortioxetine being the only antidepressant that shows a statistically significant effect compared to placebo.
All other antidepressants or antidepressant classes included in the analysis demonstrated no effect on the DSST. Comparative analysis showed that vortioxetine was more effective in terms of change in DSST from baseline compared to escitalopram and nortriptyline.
Placebo was the third most effective, further highlighting the fact that many antidepressants have less impact on DSST than placebo.
These findings confirm previous research by showing that some antidepressants improve cognitive function, and also highlight that many antidepressants and classes of antidepressants may have less impact on cognition than placebo.
Vortioxetine showed the greatest improvement in the DSST, which is in line with the results of previous studies. Furthermore, the current analysis showed that vortioxetine was the only antidepressant that demonstrated a statistically significant effect on improvement on the DSST versus placebo.
The statistically significant improvement of vortioxetine on the DSST is likely due to its unique pharmacological profile compared to other antidepressants. These mechanisms include increased glutamate neurotransmission and neuroplasticity in brain regions such as the hippocampus and prefrontal cortex.
Vortioxetine significantly improves excitatory synaptic transmission and neuroplasticity compared to SSRIs. Additionally, cognitive improvements with vortioxetine may be due to direct effects and/or indirect effects through serotonergic, noradrenergic, cholinergic, dopaminergic, and histaminergic systems.
More research is needed to understand whether pharmacological differences translate into different effects on cognition.
Importantly, none of the previous publications have quantitatively evaluated the comparative effects of antidepressants and therefore this analysis provides new insights into class effects.
There are some limitations of the current analysis. There is a lack of defined clinical recommendations for the management of cognitive dysfunction in patients with MDD, observing high variability in the reporting of cognitive outcomes. There are also methodological limitations in studies with variability in results, domains, moments of evaluations, reports of results and number of patients, preventing the generalization of the results.
In particular, vortioxetine and duloxetine had the largest number of patients included in the network trials, while the other antidepressants had far fewer patients. One of the reasons why vortioxetine shows a significant difference versus other antidepressants (despite the relatively few patients in the trials of the other antidepressants) is the generally poor performance of SSRIs and TCAs. These results should be interpreted solely as an effect on the DSST and should not be generalized to other cognitive tests during interpretation.
An important limitation of the underlying RCTs is the large variability of reported cognitive outcomes. Although there are a large number of studies exploring the effects of antidepressants on cognition, the heterogeneity of cognitive tests and outcomes used limits the analysis that can be performed in a meta-analysis.
The advantage of selecting the DSST as the sole cognitive test for MAR is that similar comparisons could be made between treatments. More research is needed using other cognitive scales. Additionally, further research on effects within different subpopulations, for example, based on age and gender, would be valuable.
In summary, although some antidepressants have demonstrated improvements in cognitive function in patients with MDD, most antidepressants have shown no effect on cognition.
Comparing the effects of a large group of antidepressants on individual cognitive measures, the DSST indicated that vortioxetine was the only antidepressant that exerted statistically significant effects on the DSST between baseline and follow-up compared to placebo and all others. analyzed antidepressants.
More research is needed to overcome the limitations associated with the large heterogeneity of cognitive measures in MDD, and future analyzes would benefit from a battery of standardized cognitive tests in MDD.
